Role And Mechanism Of MiR-124 In Regulating Tumor Growth Of Breast Cancer

Breast cancer(BC)is the second most commonly occurring cancers in the world,and is the leading cause of cancer-related deaths among women.it is estimated by International Agency for Research on Cancer(IARC)that there was 1,676,600 new cases of breast cancer and 521900 deaths resulting from breast cancer in 2012.BC is a multi-phase developmental process that includes changes in multi-gene signatures,analysis of BC genome and proteome has showed that focusing on molecular heterogeneity within BC maybe available method to identify and develop novel therapeutics.microRNAs(miRNAs)are small(approx.18-25 nt)noncoding RNAs which function as post-transcriptional regulators by negatively regulating the stability or translational efficiency of their target mRNAs.In recent years,numerous evidences have shown the vital roles of miRNAs in cancer occurrence and development,including in BC.BC miRNAs,which have an important role in the pathophysiology of the disease,facilitating invasion,metastasis,epithelial to mesenchymal transition(EMT),and maintenance of BC stem cells,have become an interesting topic in BC management.In the present study,we demonstrated that miR-124 was down-regulated in 46 pairs of human BC specimens and cell lines when compared to the adjacent normal samples and normal mammary epithelial cell lines.We constructed stable MCF7 and MDA-MB-231 cell lines expressing miR-124 and study the role of miR-124 on molecular level and animal level in BC.We found that in BC cells,the overexpression of miR-124 could significantly inhibit cells proliferation,migration and invasion,and could suppress angiogenesis,tumor growth in nude mice in vivo.In order to further study the molecular mechanism of its potential,predicted by bioinformatics software and report gene detection,we discovered that AKT2 could be a novel directly target of miR-124.AKT2(v-AKT murine thymoma viral oncogene homologue 2),an isoform of AKT family,is a significant member of the PI3K/AKT pathway.Increasing studies demonstrate the important role of AKT2 in cancers as an oncogene,which is closely associated to tumor aggressiveness by enhancing the survival,migration and invasion of cancer cells primarily.We found that miR-124 could inhibit tumor growth and angiogenesis by targeting AKT2.We also found that,in clinical BC specimens,compared with normal adjacent samples,AKT2 levels were up-regulated,and inversely correlated with miR-124 expression levels.In the present study,we demonstrated that miR-124 levels in human tumor tissues were associated with BC occurrence and development.In this study,we found that miR-124 inhibited BC progression both in vitro and in vivo,revealed that miR-124 and its new targets AKT2 were associated with BC development,illustrated the molecular mechanisms of miR-124 inhibit the BC growth by targeting AKT2.Thus,miR-124 might be used as a new diagnostic marker and therapeutic target for BC,and could be helpful in developing microRNA-based drugs for treating BC in the future.